Theranostic Strategies Research Articles

Atomic-Level Nanorings (A-NRs) Therapeutic Agent for Photoacoustic Imaging and Photothermal/Photodynamic Therapy of Cancer.

Photothermal therapy (PTT) and photodynamic therapy (PDT) have emerged as effective approaches for cancer treatment. Herein, we present atomic-level scale (0.5 nm thickness) ultrathin sulfur-doped molybdenum oxide nanorings (S-MoOx A-NRs) and with surface coating of polyethylene glycol (PEG) (PEG@S-MoOx A-NRs). This nanomaterial shows high absorbance in the near-infrared (NIR) range and can be used as a sensitive photoacoustic imaging (PAI) contrast agent. Upon NIR irradiation, the particles show high photothermal conversion and reactive oxygen species (ROS) generation, which effectively kills cancer cells both in vitro and in vivo. The PEG@S-MoOx A-NRs allow PAI and synergistic PTT/PDT therapy, which is demonstrated as a promising theranostic strategy for future cancer therapy.

Development and Non-clinical Evaluation of an 111In/225Ac Theranostic for Triple Negative Breast Cancer

The purpose of this study was to develop an Indium-111/Actinium-225 based theragnostic utilizing the tMUC1 targeting humanized antibody, TAB004, and its evaluation in a tumor bearing rodent model. Triple negative breast cancer (TNBC) is an aggressive phenotype that comprises only 15-20% of all new breast cancer cases but is responsible for a majority of related deaths. Chemotherapy is the current mainstay treatment for TNBC but side effects and drugresistance remain an issue, so development of targeted therapies for TNBC is critical. Tumor associated Mucin 1 (tMUC1), an aberrantly glycosylated transmembrane glycoprotein, is overexpressed in >90% of TNBCs and as such is an attractive target. The humanized antibody hTAB004 shows high affinity and selectivity to tMUC1 and was thus used to develop a theranostic strategy for TNBC. hTAB004 was conjugated to DOTA-NHS, purified, formulated in a metal free buffer and radiolabeled with Indium-111 or Actinium-225 to produce 111In-DOTA-hTAB004 and 225Ac-DOTA-hTAB004, respectively. The radiolabeled molecule was evaluated for stability. Retention of affinity of cold-labeled molecules was validated. In vivo and ex vivo biodistribution studies of 111In-DOTA-hTAB004 were performed in HCC70 orthotopic xenograft tumor-bearing female NSG mice (n=3) using SPECT/CT imaging over 120h. Dosimetry analysis was performed utilizing the in vivo data. Therapeutic efficacy of 225Ac-DOTA-hTAB004 was determined in HCC70 orthotopic xenograft tumorbearing female nude mice (n=5/group) by monitoring bodyweights and tumor sizes over time. DOTA-hTAB004 was labeled successfully with both Indium-111 and Actinium-225. The radiolabeled molecules were found stable in both formulation and mouse serum and the non-radioactively labeled surrogates 115In-DOTA-hTAB004 and 139La-DOTA-hTAB004 retained their affinity to tMUC1.In vivo biodistribution data revealed increased tumor accumulation of 111In-DOTA-hTAB004 over 120 h, reaching 65±15 percent of injected dose per gram (%ID/g). The next organs of significant uptake (Spleen 8.9±0.6 %ID/g and Liver 8.3±1 %ID/g) had a 7-fold lower uptake at 120 h. All mice treated with a single injection of 225Ac-DOTA-hTAB004 (500 nCi, 18 kBq) showed a complete response with tumor volumes shrinking by > 89% within 48 days. No therapy associated toxicities were seen in any of the mice outside of tail necrosis in one animal which may have been due to dose extravasation. All the control mice, which received the DOTA-hTAB004, showed continued tumor growth and had to be sacrificed by day 35. 111In-DOTA-hTAB004 biodistribution data indicates the excellent tumor targeting capabilities of hTAB004. 225Ac-DOTA-hTAB004 therapy data shows exceptional clinical benefit in mice bearing human tumors. Given this data, radiolabeled hTAB004 is a promising targeted treatment and imaging option for TNBC.

A sequential targeting nanoplatform for anaplastic thyroid carcinoma theranostics

Effective accumulation of nanoparticles (NPs) in tumor regions is one of the major motivations in nanotechnology research and that the establishment of an efficient targeting nanoplatform for the treatment of malignant tumors is urgently needed for theranostic applications. In this study, we engineered multifunctional sequential targeting NPs for achieving synergistic antiangiogenic photothermal therapy (PTT) and multimodal imaging-guided diagnosis for anaplastic thyroid carcinoma (ATC) theranostics. Antibody bevacizumab with an affinity towards vascular endothelial growth factor (VEGF) on the tumor cell surface was conjugated onto the surface of polymer NPs for VEGF targeting and antiangiogenic therapy. Encapsulated IR825 was employed as a photothermal agent (PTA) with a mitochondrial targeting capability, which further cascades NPs into mitochondria to enhance hyperthermic efficiency in the ablation of tumor cells. Importantly, the combination of bevacizumab and IR825 in a single nanosystem achieved desirable accumulations of NPs and that sequential targeted PTT combined with antiangiogenesis significantly promoted the therapeutic efficiency in eradicating tumors by near-infrared (NIR) laser irradiation. Furthermore, these NPs are extraordinary contrast agents for photoacoustic, ultrasound and fluorescence imaging applications, providing multimodal imaging capabilities for therapeutic monitoring and a precise diagnosis. Therefore, this multifunctional nanoplatform provides a promising theranostic strategy for extremely malignant ATC. Statement of significanceAnaplastic thyroid carcinoma (ATC), with extremely aggressive behavior, lacks a satisfactory therapeutic method and a comprehensive early diagnostic strategy. Herein, we successfully synthesized a sequential targeting nanoplatform (IR825@Bev-PLGA-PFP NPs) with theranostic function, which specifically binds to VEGF on the tumor cell surface and further cascades into mitochondria to achieve effective accumulation of NPs in the tumor regions. As a result, it solves the urgent demand for ATC detection and therapy. By breaking the limitation of traditional target, such as low efficacy and frequent recurrence as the results of low accumulation, sequential targeting combined with synergistic antiangiogenic PTT completely eradicates tumors without any residual tissue and side effect. Therefore, this strategy paves a solid way for further investigation in the theranostic progressing of ATC.

Tumor Microenvironment Responsive Shape-Reversal Self-Targeting Virus-Inspired Nanodrug for Imaging-Guided Near-Infrared-II Photothermal Chemotherapy.

Tumor microenvironment responsive multimodal synergistic theranostic strategies can significantly improve the therapeutic efficacy while avoiding severe side effects. Inspired by the fact that special morphology could enhance photothermal conversion efficiency (PCE) and cellular delivery, we developed an acidic tumor microenvironment responsive shape-reversal metal-organic virus-inspired nanodrug for enhancing near-infrared (NIR)-II PCE, increasing cell adhesion, and activating tumor targeting. First, a NIR-I fluorescence probe (IR825), a chemo-drug (pemetrexed, PEM), and a rare-earth metal ion (Nd(III)) were chosen to synthesize a virus-like nanodrug via coordination-driven assembly. Then, the spike-like surface of the nanodrug was further camouflaged by an acidity-sensitive poly(ethylene glycol) "shell" to create virus-core and sphere-shell hierarchical nanoassemblies, which could efficiently prevent immune clearance and prolong systemic circulation. Interestingly, the acidic tumor microenvironment could trigger the shell detachment of nanoassemblies for shape reversal to produce a virus-like surface followed by re-exposure of PEM to synergistically amplify the cellular internalization while enhancing NIR-II PCE. By utilizing the shell-detached virus-like nanodrug core, the tumor microenvironment specific enhanced NIR-II photothermal chemotherapy can be realized under the precise guidance of fluorescence/photoacoustic imaging, thereby achieving complete tumor elimination without recurrence in a single treatment cycle. We envision that integrating the tumor microenvironment responsive ability with "sphere-to-virus" shape reversal will provide a promising strategy for biomimetic targeted cancer therapy.

Theranostic Quercetin Nanoparticle for Treatment of Hepatic Fibrosis.

The progression of hepatic fibrosis can lead to cirrhosis and hepatic failure, but the development of antifibrotic drugs have faced the challenges of poor effectiveness and targeted specificity. Herein, a theranostic strategy was carried to encapsulate a natural medicine (Quercetin, QR) into hepatitis B core (HBc) protein nanocages (NCs) for imaging and targeted treatment of hepatic fibrosis. It was noted that nanoparticles (RGD-HBc/QR) with surface-displayed RGD targeting ligand exhibit a rather high selectivity toward activated HSCs via the binding affinity with integrin αvβ3, and an efficient inhibition of proliferation and activation of hepatic stellate cells (HSCs) in vitro and in vivo. Once encapsulated in quercetin-gadolinium complex and/or labeled with the NIR fluorescent probes (Cy5.5), the resulting nanoparticles (RGD-HBc/QGd) show great potential as NIR fluorescent and magnetic resonance imaging contrast agents for hepatic fibrosis in vivo. Therefore, the multifunctional integrin-targeted nanoparticles could selectively deliver QR to the activated HSCs, and may provide an effective antifibrotic theranostic strategy.

Radio-enhancement effects by radiolabeled nanoparticles

In cancer radiation therapy, dose enhancement by nanoparticles has to date been investigated only for external beam radiotherapy (EBRT). Here, we report on an in silico study of nanoparticle-enhanced radiation damage in the context of internal radionuclide therapy. We demonstrate the proof-of-principle that clinically relevant radiotherapeutic isotopes (i.e. 213Bi, 223Ra, 90Y, 177Lu, 67Cu, 64Cu and 89Zr) labeled to clinically relevant superparamagnetic iron oxide nanoparticles results in enhanced radiation damage effects localized to sub-micron scales. We find that radiation dose can be enhanced by up to 20%, vastly outperforming nanoparticle dose enhancement in conventional EBRT. Our results demonstrate that in addition to the favorable spectral characteristics of the isotopes and their proximity to the nanoparticles, clustering of the nanoparticles results in a nonlinear collective effect that amplifies nanoscale radiation damage effects by electron-mediated inter-nanoparticle interactions. In this way, optimal radio-enhancement is achieved when the inter-nanoparticle distance is less than the mean range of the secondary electrons. For the radioisotopes studied here, this corresponds to inter-nanoparticle distances <50 nm, with the strongest effects within 20 nm. The results of this study suggest that radiolabeled nanoparticles offer a novel and potentially highly effective platform for developing next-generation theranostic strategies for cancer medicine.

Severe influenza: overview in critically ill patients.

Overview of influenza infection, focusing on outcome and complications in critically ill patients. We also discuss relevant elements in immunopathogenesis and their role as predictors of severity. Pandemic influenza A (H1N1) virus circulates seasonally and remains the predominant subtype among intensive care patients. Mortality in acute respiratory failure (ARF) is around 20%, independent of influenza subtypes. During severe infection, the imbalance between pro-inflammatory and anti-inflammatory molecules, such as Th1 and Th17 cytokines, is associated with complicated infections and mortality. Primary viral pneumonia presents in more than 70% of ICU influenza patients and more than 50% develop acute respiratory distress syndrome. Bacterial secondary infection occurs in 20% of severe cases and Streptococcus pneumoniae and Staphylococcus aureus remain the prevalent pathogens. Myocarditis and late-onset cardiovascular complications are associated with mortality. Antiviral therapy within 48 h after onset, avoidance of corticosteroids and rescue therapies for ARF or myocarditis, such as extracorporeal membrane oxygenation, improve survival. The present review summarizes current knowledge on pathogenesis and clinical manifestations of severe influenza. Immunological dysfunction during viral infection correlates with severity and mortality among ICU patients. A theranostics strategy should be implemented to improve outcomes.

Lab on the eye: A review of tear-based wearable devices for medical use and health management.

Wearable sensors have garnered considerable interest because of their great promise in terms of personalized health and disease management. Tears are a superior target for wireless, non-invasive wearable devices, and tear-based platforms have developed rapidly over the past decade. Although an increasing number of tear analytes have been found to be associated with multiple diseases, glucose still serves as a main target for tear-based wearable devices. There has been much investment and efforts to develop tear-based wearable biosensors, with contact lens-based and spring-like sensors flourishing commercially. Current efforts have moved past ocular and systematic disease markers to nutrients and chemicals. Moreover, tear-based wearable devices also have the potential to treat some ocular diseases. This review discusses aspects of tear-based wearable devices and it emphasizes that strict clinical validation is needed before such platforms enter the market. Multifunctional and theranostic strategies would further broaden their clinical use in the future.

High-resolution bimodal imaging and potent antibiotic/photodynamic synergistic therapy for osteomyelitis with a bacterial inflammation-specific versatile agent

Unsatisfactory diagnosis and therapy of osteomyelitis are still common but challenging issues for clinicians. To overcome these problems, a bacterial inflammation-specific multifunctional agent, denoted bovine serum albumin-manganese dioxide-ubiquicidin29-41-indocyanine green (ICG) -gentamicin (BMUIG), was synthesized for combined high-resolution bimodal imaging and antibiotic/photodynamic therapy for osteomyelitis. BMUIG binding affinity and antibacterial ability were assessed by using Staphylococcus aureus (S. aureus). Photoacoustic/magnetic resonance imaging was performed on a mouse model of acute osteomyelitis after intravenous injection of BMUIG. Then, myelitis-bearing mice were treated with antibiotic/photodynamic combination therapy. BMUIG specifically targeted S. aureus in comparison with non-targeted agents. In the osteomyelitis model, the infection area was identified accurately and quickly through ICG-based photoacoustic imaging and Mn2+-based T1 magnetic resonance imaging after injection of BMUIG. Furthermore, the manganese dioxide in BMUIG reacted with the locally produced hydrogen peroxide under acidic inflammatory conditions, continuously generating oxygen for enhanced photodynamic therapy. In combination with low-dose gentamicin, a synergistic antibacterial effect was observed and bone infection was resolved. In summary, a non-invasive accurate diagnosis and effective synergistic therapy for osteomyelitis was successfully developed using a bacterial inflammation-specific versatile agent, which would provide a sound theranostic strategy for common infectious diseases. Statement of SignificanceOsteomyelitis is one of the most serious consequences in orthopedics. However, its inaccurate diagnosis and low-effective antibiotic treatment are still common but challenging issues for clinicians. To overcome these problems, we uniquely designed a bacterial inflammation-specific multifunctional nanoagent, bovine serum albumin-manganese dioxide-ubiquicidin29-41-indocyanine green-gentamicin (BMUIG), for high-resolution bimodal imaging and antibiotic/photodynamic combined therapy of osteomyelitis. Herein, high-resolution imaging technologies refer to classic magnetic resonance imaging and emerging photoacoustic imaging. Photodynamic therapy is subtly introduced because of its safe and effective killing mechanism, which can synergize the bactericidal effect of antibiotics. As a result, we successfully realize non-invasive accurate diagnosis and effective synergistic therapy for osteomyelitis by virtue of the bacterial inflammation-specific versatile agent, which will serve as a promising candidate for sound theranostics in common infectious diseases.

A GSH-Gated DNA Nanodevice for Tumor-Specific Signal Amplification of microRNA and MR Imaging-Guided Theranostics.

Developing tumor-responsive diagnosis and therapy strategies for tumor theranostics is still a challenge owing to their high accuracy and specificity. Herein, an AND logic gated-DNA nanodevice, based on the fluorescence nucleic acid probe and polymer-modified MnO2 nanosheets, for glutathione (GSH)-gated miRNA-21 signal amplification and GSH-activated magnetic resonance (MR) imaging-guided chemodynamic therapy (CDT) is reported. In the presence of overexpressed miRNA and GSH (tumor cells), the nanodevice can be in situ activated and release significantly amplified fluorescence signals and MR signals. Conversely, the fluorescence signal is quenched and MR signal remains at the background level with low miRNA and GSH (normal cells), efficiently reducing the false-positive signals by more than 50%. Under the guide of miRNA profiling and MR imaging, the tumor-responsive hydroxyl radical (·OH) can effectively kill tumor cells. Furthermore, the nanodevice shows catalase-like activity and glucose oxidase-like activity with the performance of O2 production and glucose consumption. This is the first time to fabricate a tumor-responsive theranostic DNA nanodevice with tumor-specific signal amplification of microRNA and GSH-activated MR imaging for CDT, potential hypoxia relief and starvation therapy, which provides a new insight for designing smart theranostic strategies.

Engineering patient-specific cancer immunotherapies.

Research into the immunological processes implicated in cancer has yielded a basis for the range of immunotherapies that are now considered the fourth pillar of cancer treatment (alongside surgery, radiotherapy and chemotherapy). For some aggressive cancers, such as advanced non-small-cell lung carcinoma, combination immunotherapies have resulted in unprecedented treatment efficacy for responding patients, and have become frontline therapies. Individualized immunotherapy, enabled by the identification of patient-specific mutations, neoantigens and biomarkers, and facilitated by advances in genomics and proteomics, promises to broaden the responder patient population. In this Perspective, we give an overview of immunotherapies leveraging engineering approaches, including the design of biomaterials, delivery strategies and nanotechnology solutions, for the realization of individualized cancer treatments such as nanoparticle vaccines customized with neoantigens, cell therapies based on patient-derived dendritic cells and T cells, and combinations of theranostic strategies. Developments in precision cancer immunotherapy will increasingly rely on the adoption of engineering principles.

From Targeting Somatic Mutations to Finding Inherited Cancer Predispositions: The Other Side of the Coin.

The expanding use of tumor genome analysis by next generation sequencing to drive target therapies has led to increased germline findings in genes predisposing to hereditary cancer. These putative germline findings obtained from theranostic analyses, such as BRCA1/2 gene testing, large panels, whole-exome, or whole-genome sequencing, need to be managed carefully and in an anticipated way with the patient. Before the genetic analysis of a tumor, specific information should be given to patients, who should be aware that the results may have extra-therapeutic medical issues for themselves and relatives. We previously published a list of 36 actionable genes predisposing to cancer for which informing the patient is recommended prior to pangenomic germline analysis because of available screening or preventive strategies. Here, we report clinical practice considerations and schemes for managing germline findings in tumor analyses, including written informed consent and a multidisciplinary approach involving an oncologist, molecular biologist/pathologist, and geneticist in case of germline findings. A somatic result showing a deleterious mutation in a known predisposing gene in a patient who has consented to this purpose should result in referral to a geneticist who is part of the multidisciplinary team. At any time of the somatic analysis process, the patient may have access to a geneticist consultation if additional information is required. This framework will optimally manage both personalized theranostic issues and specific preventive strategies for individuals and relatives; it will also simplify and accelerate the process of genetic testing.

Gamma Emitters in Pancreatic Endocrine Tumors Imaging in the PET Era: Is there a Clinical Space for 99mTc-peptides?

Pancreatic Neuroendocrine Tumors (PNETs) are rare neoplasms, sporadic or familial, even being part of a syndrome. Their diagnosis is based on symptoms, hormonal disorders or may be fortuitous. The role of Nuclear Medicine is important, mainly because of the possibility of a theranostic strategy. This approach is allowed by the availability of biochemical agents, which may be labeled with radionuclides suitable for diagnostic or therapeutic purposes, showing almost identical pharmacokinetics. The major role for radiopharmaceuticals is connected with radiolabeled Somatostatin Analogues (SSA), since somatostatin receptors are highly expressed on some of the neoplastic cell types. Nowadays, in the category of radiolabeled SSA, although 111In-pentetreotide, firstly commercially proposed, is still used, the best choice for diagnosis is related to the so called DOTAPET radiotracers labeled with 68-Gallium (Ga), such as 68Ga-DOTATATE, 68Ga-DOTANOC, and 68Ga-DOTATOC. More recently, labeling with 64-Copper (Cu) (64Cu-DOTATATE) has also been proposed. In this review, we discuss the clinical interest of a SAA (Tektrotyd©) radiolabeled with 99mTc, a gamma emitter with better characteristics, with respect to 111Indium, radiolabeling Octreoscan ©. By comparing both pharmacokinetics and pharmacodynamics of Octreoscan©, Tektrotyd© and PET DOTA-peptides, on the basis of literature data and of our own experience, we tried to highlight these topics to stimulate further studies, individuating actual clinical indications for all of these radiotracers. In our opinion, Tektrotyd© could already find its applicative dimension in the daily practice of NETs, either pancreatic or not, at least in centers without a PET/CT or a 68Ga generator. Because of wider availability, a lower cost, and a longer decay, compared with respect to peptides labeled with 68Ga, it could be also proposed, in a theranostic context, for a dosimetry evaluation of patients undergoing Peptide Receptor Radionuclide Therapy (PRRT), and for non-oncologic indications of radiolabelled SSA. In this direction, and for a more rigorous cost/effective evaluation, more precisely individuating its clinical role, further studies are needed.

Abstract 1135: Dextran based nanoparticles for immunotheranostics of prostate cancer

Abstract Introduction: Targeted nanoparticles (NPs) containing imaging reporters provide exciting options for cancer-specific delivery of siRNA to downregulate specific pathways in theranostic strategies. We recently developed a biodegradable modified dextran NP to deliver effectively siRNA and downregulate the target in vivo (1). Here we have developed a prostate specific membrane antigen (PSMA)-targeted dextran NP to deliver siRNA to downregulate PD-L1 in PSMA expressing prostate cancer (PCa) cells for immunotheranostics. In proof-of-principle studies, the NP was decorated with an optical imaging reporter to allow noninvasive detection in vivo, and evaluated in PC3 human PCa cells genetically engineered to overexpress PSMA (PC3-PIP) and in non-PSMA expressing PC3-Flu cells. Since castration-resistant PCa cells express PSMA, the ability to down regulate PD-L1 specifically may prevent these cancer cells from evading immune surveillance, resulting in their destruction by the immune system. Methods: For mRNA and protein analysis, PSMA overexpressing PC3-PIP cells and low PSMA expressing PC3-Flu cells were treated with dextran NPs with PD-L1 siRNA or PBS. 6h later, IFNγ (10 ng/mL) or PBS was added to the medium. Cells were collected, and proteins and mRNA extracted, 24h after NP/PBS treatment. Total RNA was isolated, and cDNA prepared following standard protocols, with q-RT-PCR performed for PD-L1 expression. Western blots were probed with anti-PD-L1, and anti-PSMA antibodies. For in vivo studies, PC3-PIP and PC3-Flu tumors were inoculated bilaterally in the flanks of male SCID mice. Once tumors reached ~200 mm3, dextran NPs siRNA with PSMA binding peptide were injected intravenously. Dosage and frequency of IFNγ injection in vivo was established, and bio distribution studies performed. Tumor samples were harvested and processed for mRNA and protein to detect PD-L1 expression. Results and Conclusion: Specificity of the PSMA-targeted dextran NP delivery was confirmed by PSMA-dependent retention of the NPs following fluorescent imaging of PC3-PIP and Flu cells. We next assessed the ability of the dextran NPs carrying PD-L1 siRNA to down regulate PD-L1 expression in PC3-PIP and PC3-Flu cells. Studies were performed with or without pre-activation of the cells with IFNγ. q-RT-PCR and western blots analysis confirmed a clear decrease of PD-L1 after NP treatment in PC3-PIP and PC3-Flu cells. Effective NP delivery was confirmed in tumors with optical imaging, both in vivo and ex vivo in excised organs. Ongoing studies are characterizing PD-L1 downregulation in tumors in vivo following treatment with PSMA-targeted dextran NPs delivering PD-L1 siRNA.

Abstract LB-281: Development and non-clinical evaluation of an111In/225Ac theranostic for triple negative breast cancer

Abstract Purpose: The purpose of this study was to develop an Indium-111/Actinium-225 based theragnostic utilizing the tMUC1 targeting humanized antibody, TAB004, and its evaluation in a tumor bearing rodent model. Triple negative breast cancer (TNBC) is an aggressive phenotype that comprises only 15-20% of all new breast cancer cases but is responsible for a majority of related deaths. Chemotherapy is the current mainstay treatment for TNBC but side effects and drug-resistance remain an issue, so development of targeted therapies for TNBC is critical. Tumor associated Mucin 1 (tMUC1), an aberrantly glycosylated transmembrane glycoprotein, is overexpressed in &amp;gt;90% of TNBCs and as such is an attractive target. The humanized antibody hTAB004 shows high affinity and selectivity to tMUC1 and was thus used to develop a theranostic strategy for TNBC. Method: hTAB004 was conjugated to DOTA-NHS, purified, formulated in a metal free buffer and radiolabeled with Indium-111 or Actinium-225 to produce 111In-DOTA-hTAB004 and 225Ac-DOTA-hTAB004, respectively. The radiolabeled molecule was evaluated for stability. Retention of affinity of cold-labeled molecules was validated. In vivo and ex vivo biodistribution studies of 111In-DOTA-hTAB004 were performed in HCC70 orthotopic xenograft tumor-bearing female NSG mice (n=3) using SPECT/CT imaging over 120h. Dosimetry analysis was performed utilizing the in vivo data. Therapeutic efficacy of 225Ac-DOTA-hTAB004 was determined in HCC70 orthotopic xenograft tumor-bearing female nude mice (n=5/group) by monitoring bodyweights and tumor sizes over time. Results: DOTA-hTAB004 was labeled successfully with both Indium-111 and Actinium-225. The radiolabeled molecules were found stable in both formulation and mouse serum and the non-radioactively labeled surrogates 115In-DOTA-hTAB004 and 139La-DOTA-hTAB004 retained their affinity to tMUC1. In vivo biodistribution data revealed increased tumor accumulation of 111In-DOTA-hTAB004 over 120 h, reaching 65±15 percent of injected dose per gram (%ID/g). The next organs of significant uptake (Spleen 8.9±0.6 %ID/g and Liver 8.3±1 %ID/g) had a 7-fold lower uptake at 120 h. All mice treated with a single injection of 225Ac-DOTA-hTAB004 (500 nCi, 18 kBq) showed a complete response with tumor volumes shrinking by &amp;gt; 89% within 48 days. No therapy associated toxicities were seen in any of the mice outside of tail necrosis in one animal which may have been due to dose extravasation. All the control mice, which received the DOTA-hTAB004, showed continued tumor growth and had to be sacrificed by day 35. Conclusions 111In-DOTA-hTAB004 biodistribution data indicates the excellent tumor targeting capabilities of hTAB004. 225Ac-DOTA-hTAB004 therapy data shows exceptional clinical benefit in mice bearing human tumors. Given this data, radiolabeled hTAB004 is a promising targeted treatment and imaging option for TNBC. Citation Format: ohad ilovich, Vanessa Kelly, Shu-ta Wu, Vijay Gottumukkala, Richard Coelho, Rahul Puri, Pinku Mukherjee. Development and non-clinical evaluation of an111In/225Ac theranostic for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-281.

Boosting Postsurgical Outcomes of Orthotopic Hepatocellular Carcinoma via an EpCAM‐Targeting Theranostic Nanoparticle

AbstractHepatectomy is one of the main treatments for hepatocellular carcinoma (HCC). However, because microscopic tumor residues are often present after surgery, the recurrence rate of HCC remains extremely high. A multimodality imaging‐guided multifunctional nanoparticle, indocyanine‐green–gadolinium–copper sulfide@bovine‐serum‐albumin–epithelial‐cell‐adhesion molecule (EpCAM), is developed for HCC treatment based on a novel theranostic strategy. After intravenous injection of these nanoparticles into HCC‐bearing mice, remarkably selective accumulation and highly efficient retention of the nanoparticles in tumor sites are observed. This is due to the EpCAM's specific targeting ability, which also results in enhanced HCC contrast in a tri‐modal visualization, which unites magnetic resonance, photoacoustic, and fluorescence imaging. Moreover, nanoparticle uptake into the HCC allows photothermal therapy (PTT) as an interoperative adjuvant strategy for further eliminating possible microscopic residues and boosting HCC surgery outcomes. This theranostic strategy not only helps with precise diagnosis of HCC but enables intraoperatively imaging guidance for accurate tumor resection. Moreover, postoperation longitudinal observation demonstrates that intraoperative imaging‐guided resection alongside a PTT‐integrated treatment strategy can result in a significant improvement of overall survival rate. These multifunctional EpCAM‐targeting nanoparticles may respresent a novel theranostic strategy to improve postsurgical HCC treatment.

NIR-responsive nanoplatform for pre/intraoperative image-guided carcinoma surgery and photothermal ablation of residual tumor tissue

Local recurrence is common among patients with advanced cancer who have undergone surgery. Here, we developed a new surgical treatment for cancer based on a nanoparticle that loaded a near-infrared dye (IR780 iodide) and perfluorooctyl bromide into liposomes (NP-IR780). In an orthotopic breast cancer mouse model, NP-IR780 was demonstrated to have excellent tumor-targeting ability due to the selective tumor accumulation of IR780 iodide and the enhanced permeation and retention effect of the nanoparticle. With the excellent targeting ability, concurrent computed tomography and photoacoustic imaging were achieved for preoperative planning. In particular, NP-IR780 could serve as a tumor indicator for near-infrared fluorescence image-guided precise resection of lesions during surgery. Importantly, residual tumors could be ablated through intraoperative photothermal therapy without obvious recurrence. This work provides a theranostic strategy that significantly improved the survival of mice through pre/intraoperative image-guided tumor resection and subsequent photothermal therapy of residual lesions.

Design and synthesis of dynamic nano assemblies for biomedical applications

Nanotechnology has emerged as a powerful tool and plays an important role in the development of biomedicine. The construction of novel nanomaterials to optimize their functionality in lesions is the key issue in nanomedicine. Smart nanoassemblies have received intensive attention due to their tunable function intrigued by certain stimuli. Especially for the diagnosis and treatment of tumors, the design and synthesis of dynamic nanoassemblies based on the microenvironment of tumors can achieve the dynamic transformation of their structures in vivo , and consequently amplify the imaging signals, enhance the therapeutic efficiency and improve the biosafety, which provides a new strategy for intelligent theranostics. In this review, we summarize the advanced assembly strategies and discuss the application of dynamic nanoassemblies that response to endogenous stimuli (pH, enzymes and redox) in the diagnosis and treatment of tumor.

Intelligent Hollow Pt-CuS Janus Architecture for Synergistic Catalysis-Enhanced Sonodynamic and Photothermal Cancer Therapy.

As a noninvasive treatment modality, ultrasound (US)-triggered sonodynamic therapy (SDT) shows broad and promising applications to overcome the drawbacks of traditional photodynamic therapy (PDT) in combating cancer. However, the SDT efficacy is still not satisfactory without oxygen (O2) assistance. In addition, there is also much space to explore the SDT-based synergistic therapeutic modalities. Herein, a novel Pt-CuS Janus composed of hollow semiconductor CuS and noble metallic Pt was rationally designed and successfully synthesized. The hollow CuS shows a large inner cavity for loading sonosensitizer molecules (tetra-(4-aminophenyl) porphyrin, TAPP) to implement SDT. Moreover, the deposition of Pt not only enhances photothermal performance compared with those of CuS nanoparticles (NPs) due to the effect of the local electric field enhancement but also possesses nanozyme activity for catalyzing decomposition of endogenous overexpressed hydrogen peroxide (H2O2) to produce O2 that can overcome tumor hypoxia and augment the SDT-induced highly toxic reactive oxygen species (ROS) production for efficient cancer cell apoptosis. Importantly, the generated heat of Pt-CuS by 808 nm laser irradiation can accelerate the catalytic activity of Pt and elevate the O2 level that further facilitates SDT efficacy. Interestingly, the thermally sensitive copolymer coated around the Janus can act as a smart switch to regulate the catalytic ability of Pt and control TAPP release that has a significant effect on modulating the therapeutic effect. The synergistic catalysis-enhanced SDT efficiency and highly photothermal effect almost realized complete tumor resection without obvious reoccurrence and simultaneously displayed a highly therapeutic biosafety. Furthermore, the high optical absorbance allows the as-synthesized Pt-CuS Janus for photoacoustic (PA) imaging and NIR thermal imaging. This work develops a versatile nanoplatform for a multifunctional theranostic strategy and broadens the biological applications by rationally designing their structure.

Concurrent Osteosarcoma Theranostic Strategy Using Contrast-Enhanced Ultrasound and Drug-Loaded Bubbles.

Osteosarcoma (OS) is the most common bone tumor in children and teenagers. The multidrug resistant property of OS produces a major obstacle to chemotherapy, since the effective drug dose cannot be achieved via conventional drug delivery routes without serious systemic cytotoxicity. Microbubbles in conjunction with ultrasound (US) has recently been shown to spatially and temporally permeabilize the cellular membrane, promoting drug penetration into tumors. Here, we investigated whether drug (doxorubicin, DOX)-loaded bubbles (DOX-bubbles) can serve as drug-loaded carriers in combination with US in order to facilitate tumor drug delivery. The proposed bubbles have a high payload capacity (efficiency of 69.4 ± 9.1%, payload of 1.4 mg/mL) for DOX. In vitro data revealed that when used in combination with US (1-MHz), these DOX-bubbles facilitate DOX entering into tumor cells. In tumor-bearing animals, DOX-bubbles + US could provide 3.7-fold suppression of tumor growth compared with the group without insonation (1.8 ± 0.9 cm3 vs. 8.5 ± 2.2 cm3) because of the acceleration of DOX-induced tumor necrosis. In the meantime, the tumor perfusion and volume can be monitored by DOX-bubbles with contrast-enhanced ultrasound imaging. Our data provide useful information in support of translating the use of theranostic US-responsive bubbles for regulated tumor drug delivery into clinical use.